PAC-1 and its derivative WF-210 Inhibit Angiogenesis by inhibiting VEGF/VEGFR pathway

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Procaspase Activating Compound-1 (PAC-1) and its derivative WF-210 are known to induce apoptosis in cancer cells.
• The precise mechanisms underlying the anti-cancer effects of PAC-1 and WF-210, particularly concerning tumor angiogenesis, require further elucidation.

Purpose of the Study:

• To investigate the anti-angiogenic mechanisms of PAC-1 and WF-210.
• To explore the effects of PAC-1 and WF-210 on tumor growth and related cellular processes beyond apoptosis induction.

Main Methods:

• In vitro assays using human umbilical vascular endothelial cells (HUVECs) to assess proliferation, invasion, and tube formation.
• Ex vivo assays including rat aortic ring sprouting and in vivo Matrigel plug assay to evaluate vascularization.
• Western blot analysis to examine the phosphorylation status of VEGFR2 and downstream signaling proteins (c-Src, FAK, AKT).
• In vivo studies using xenograft mouse models (subcutaneous and orthotopic) to assess tumor growth and angiogenesis.
• Cellular assays to evaluate cancer stemness and autophagy flux in U-87 cells.

Main Results:

• PAC-1 and WF-210 significantly inhibited VEGF-induced HUVEC proliferation, invasion, and tube formation.
• Both compounds suppressed VEGF-induced vessel sprouting in rat aortic rings and vascularization in the Matrigel plug assay.
• PAC-1 and WF-210 reduced VEGFR2 phosphorylation and downstream signaling in HUVECs and U-87 cells.
• In vivo, PAC-1 and WF-210 demonstrated significant inhibition of tumor growth and angiogenesis in xenograft models.
• PAC-1 and WF-210 were found to inhibit cancer stemness and induce autophagy flux in U-87 cells.

Conclusions:

• PAC-1 and WF-210 possess potent anti-angiogenic properties, acting through the VEGFR2 signaling pathway.
• Beyond apoptosis induction, these compounds exhibit anti-tumor effects by inhibiting tumor growth, angiogenesis, stemness, and modulating autophagy.
• The findings support the potential clinical application of PAC-1 and WF-210 as anti-cancer agents with multifaceted mechanisms of action.